Abstract
BackgroundCryptopleurine, a phenanthroquinolizidine alkaloid, was known to exhibit anticancer activity; however, the underlying mechanism is poorly understood. Because the nuclear factor-κB (NF-κB) transcription factors control many physiological processes including inflammation, immunity, and development and progression of cancer, we investigated the effects of cryptopleurine on tumor necrosis factor alpha (TNF-α)-induced NF-κB activation pathway and on the expression of NF-κB-regulated gene products associated with many pathophysiological processes.Methodology and Principal FindingMDA-MB231, MDA-MB435, MCF-7, HEK293, RAW264.7 and Hep3B cells were used to examine cryptopleurine's effect on the NF-κB activation pathway. Major assays were promoter-reporter gene assay, electrophoretic mobility shift assay (EMSA), in vitro immune complex kinase assay, real-time PCR, Western blot analysis, and Matrigel invasion assay. Experiments documenting cell proliferation and apoptosis were analyzed by MTT method and flow cytometry, respectively. The results indicated that cryptopleurine suppressed the NF-κB activation through the inhibition of IκB kinase (IKK) activation, thereby blocking the phosphorylation and degradation of the inhibitor of NF-κB alpha (IκBα) and the nuclear translocation and DNA-binding activity of p65. The suppression of NF-κB by cryptopleurine led to the down-regulation of gene products involved in inflammation, cell survival, proliferation, invasion, and angiogenesis.Conclusions and SignificanceOur results show that cryptopleurine inhibited NF-κB activation pathway, which leads to inhibition of inflammation, proliferation, and invasion, as well as potentiation of apoptosis. Our findings provide a new insight into the molecular mechanisms and a potential application of cryptopleurine for inflammatory diseases as well as certain cancers associated with abnormal NF-κB activation.
Highlights
The nuclear factor-kB (NF-kB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and tumor invasion [1,2,3]
Our results show that cryptopleurine inhibited NF-kB activation pathway, which leads to inhibition of inflammation, proliferation, and invasion, as well as potentiation of apoptosis
In an effort to unravel the molecular mechanism of cryptopleurine (Fig. 1A), we investgated its effects on tumor necrosis factor alpha (TNF-a)-induced NF-kB activation pathway
Summary
The nuclear factor-kB (NF-kB) transcription factors control many physiological processes including inflammation, immunity, apoptosis, and tumor invasion [1,2,3]. In addition to regulating the expression of genes important for immune and inflammatory responses, NF-kB controls the transcription of genes that are critical in the early and late stages of aggressive cancers, including cyclooxygenase-2 (COX-2), cyclinD1, apoptosis suppressor proteins such as cellular inhibitor of apoptosis 1 (cIAP1), B-cell lymphoma 2 (Bcl2), TNF-a receptor-associated factor 2 (TRAF2), cellular FLICE inhibitory protein (FLIP), and genes required for invasion and angiogenesis such as inter-cellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase (MMP-9) and vascular endothelial growth factor (VEGF) [7,8]. Because the nuclear factor-kB (NF-kB) transcription factors control many physiological processes including inflammation, immunity, and development and progression of cancer, we investigated the effects of cryptopleurine on tumor necrosis factor alpha (TNF-a)-induced NF-kB activation pathway and on the expression of NF-kB-regulated gene products associated with many pathophysiological processes
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